Lung cancer is the most common cause of cancer death in the United States and is very ineffectively treated, with a less than 15% 5 year survival. This application proposes a partnering of premiere institutions based in the Lung Cancer SPORE program to determine how the information derived from comprehensive molecular analyses can be used to improve patient care and ultimately, patient outcomes. We propose to evaluate the potential clinical usefulness of several molecular signatures already developed using a variety of molecular analysis technologies, including DNA, RNA and protein-based technologies addressing both diagnostic and predictive signatures. The diagnostic profile we propose to test uses serum proteomics to discriminate patients with cancer from those without cancer with goal to reduce the number of futile thoracotomies. The predictive profiles we propose to test include survival and occult nodal status involvement, useful for in risk assessment, and genomic, cDNA and proteomic profiles predicting response to chemotherapy and EGFr targeted therapeutics. Important markers in proteomic profiles will be identified, and together with genomic and cDNA markers, clinically feasible assays will be developed and their robustness tested in prospective studies.